Biowarfare agents, like chemical weapons, have often been termed the "poor man's atomic bomb," because of their potential for devastation and the relative ease with which they can be weaponized at low cost. Yersinia pestis is an infectious agent of particular concern because it has been very effectively weaponized and causes debilitating and often fatal illnesses -bubonic and pneumonic plague. While antibiotic treatments exist to counter biological attack with this agent, there are serious drawbacks with the available options. Strains of plague have already arisen naturally, which are resistant to most antibiotic compounds. Antibiotics to combat plague can also be countered easily by genetically engineered strains, which harbor resistance genes to these compounds. It is likely that this has been extensively pursued in the former Soviet bioweapons program. It is therefore a matter of public health and potentially national security to protect the population from the possible use of this agent. One way to do this is, to develop a new class of therapeutic compounds that can be used to treat an exposed or ailing population. In particular, developing drugs that inhibit virulence mechanisms of this pathogen instead of targeting vital processes would represent a novel class of antibacterial with many advantages over existing therapies. The overall goal of this application is to test the efficacy of using phage display peptide technologies to identify novel drugs that impair the virulence mechanisms of plague bacterium. Specifically, we wish to: (1) use phage display to identify high affinity peptide binders for molecules central to the virulence system of Y. pestis, (2) test these peptides for their ability to impair biochemical function of the pathogen's proteins and (3) use structural biology to examine the nature of the inhibitor-protein interactions in order to improve by rational design the biological activity of the peptides. These studies are therefore intended as a pilot experiment, which would lead to a broader initiative to examine the efficacy of these inhibitors in vivo, and to bring them to the drug development stage. The threats of biological attack require that a variety of therapies be available as countermeasures. These studies may lead to the discovery of novel classes of antimicrobial compounds, which may serve to combat these emerging threats.